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Monday, 21 August 2017

Mitchondrial Replacement Therapy (MRT) – sometimes referred to with its headline name "Three Parent Babies" – is an innovative, in humans yet unproven, reproductive genetic technology, by which it is hoped that a more effective avoidance of having children with severe mitochondrial hereditary disease (as a rule extremely severe, untreatable and lethal). MRT is controversial both as assisted reproductive technologies are controversial, primarily among certain religious groups, and because it is the first example of hereditary genetic modification of human beings – so-called germline genetic modification – that has been seriously contemplated. A nice summary of the scientific and ethical complexities involved can be found here. The last couple of years, ethical, legal and scientific debate about whether or not human trials of this experimental technique should be allowed has surged, and special legal provisions have been created for this purpose in the U.K., as well as some US states. However, the leading reproductive researchers in the UK and US just stepping up to make an opportunity out of this new legal room were quickly overtaken by the less prominent colleague of Dr. John Zhang, from a US private fertility clinic, who almost a year ago reported a human MRT experiment conducted at a Mexican clinic in order to duck US regulatory oversight.

Already from the start, ethical and regulatory questionmarks have surrounded this experiment. First, objections have been raised about the ethics of Dr. Zhang to create MRT embryos in the US to then be moved to foreign soil in order to circumvent US regulatory frameworks and scientific guidelines for MRT. Second, while Dr. Zhang had described why Mexico was chosen as the country to host the experiment by claiming that “there are no rules” regarding MRT there, subsequent legal analysis by my bioethics scholarly colleagues César Palacios Gonzalez and María de Jesús Medina Arellano has revealed that the experiment very likely breached a number of Mexican legal statutes related to research and reproductive medicine. A popular presentation of this finding can be accessed here.

In the meantime, the US Food and Drug Administration, yes, the mighty FDA, has apparently been silently probing the matter with regard to Dr. Zangh's relationship to US federal law. For just a few days ago, Mary A. Malarkey, Director of the FDA's Office of Compliance and Biologics Quality, sent a briskly phrased (to say the least) official letter to Dr. Zhang, enumerating a number of US federal legal violations allegedly involved in the Mexico MRT adventure. I have uploaded the letter to to Google and made it available for anyone to view and share, here. Among the allegations made in this letter are the following:

... you are using MRT to form a genetically modified embryo, which is
subject to FDA’s regulations with respect to human cells, tissues, or cellular or tissue based
products (HCT/Ps) under 21 CFR Part 1271, issued under authority of section 361 of the Public
Health Service Act (PHS Act [42 U.S.C. 264]). HCT/Ps that do not meet all of the criteria in 21
CFR 1271.10(a) and do not qualify for any exceptions in section 1271.15, are subject to
additional regulation, including appropriate premarket review.

The genetically modified embryo that you formed using MRT does not meet all the criteria in 21
CFR 1271.10(a) and does not qualify for any exceptions. /... /

[The HCT/P is] also regulated as a drug as defined under section 201(g)
of the Federal Food, Drug, and Cosmetic Act (FD&C Act) [21 U.S.C. 321(g)], and a biological
product as defined in section 351(i) of the PHS Act [42 U.S.C. 262(i). Specifically, your
processing constitutes more than minimal manipulation of cells or nonstructural tissues, as
defined in 21 CFR 1271(f)(2)

To lawfully market a drug that is also a biologic, a valid biologics license must be in effect [42
U.S.C. 262(a)]. Such licenses are issued only after a demonstration of safety, purity, and
potency. While in the development stage, such biological drugs may be distributed for clinical
use in humans only if the sponsor has an IND application in effect as specified by FDA
regulations (21 U.S.C. 355(i); 42 U.S.C. 262(a)(3); 21 CFR Part 312). The MRT-produced
HCT/P is not the subject of an approved biologics license application (BLA) nor is there an IND
in effect. / ... /

Nor is exportation permitted unless it meets the requirements of an applicable
export exemption.

/ ... / your export at issue
here did not meet the requirements of any of these export exemptions. / ... /

The Director signs off by noting:

This letter is not intended to be an all-inclusive list of violations. It is your responsibility to
ensure full compliance with the FD&C Act and the PHS Act and their implementing regulations.

We request that you notify this office, in writing, of the steps you have taken or will take to
address the violation noted above and to prevent recurrence.

While I am cautiously positive to having well-regulated legal room for MRT trials, I have to say I found Dr. Zhang's maverick action very ill-conceived from the start. While the experiment has been subsequently reported scientifically, it is not part of any controlled and planned experimental series that could contribute to the formation of a solid body of scientific evidence to either substantiate or rebut the hypothesis that MRT is a viable medical procedure. Nor was it done in response to any sort of dire medical need, but solely as an attempt to overcome efficiency problems in IVF, thereby lacking any of the ethical justification usually cited as the main reason to allow for human MRT trials. Moreover, as there was no research ethical review, no check has been applied to the consent procedure, making it very likely that the couple who were the patients have been exposed to what is known as the therapeutic misconception. Therefore, the experiment brings to mind the sorry tale of what has become of the once red-hot scientific field of stem cell therapy, nowadays mostly ruined and disreputed by gung-ho experimenters and unchecked, semi-fraudulent commercial operations preying on vulnerable people's desperation in a hunt for money and personal glory. If germ-line gene therapy is to be allowed and able to develop out of MRT experiments, it has to proceed within a very rigid and tight oversight, both scientifically and ethically. Stunts like the one of Dr. Zhang constitute a threat to that. Therefore, I'm very pleased to see FDA yank whatever legal leash it has as hard as it can, and I hope the scientific community will do the same. As a first step, a retraction of the article in Reproductive Biomedicine Online due to false statements regarding ethical and legal status of the reported trial may be in order?

Sunday, 4 June 2017

As I reported before, the Centre for Antibiotic Resistance Research, CARe, at the University of Gothenburg, is organising a free of charge symposium this fall on the theme of Ethics and Value Challenges in Antibiotic Resistance Management, Policy and Research.

Participation is free and open to professionals, officials, policy makers, researchers and interested members of the public, but requires pre-registration. Get more information and sign up here.

Taking place November 15-16, this is a unique opportunity for anyone interested in the topic of antibiotic resistance to learn from and interact with world-leading researchers in this area, representing disciplines such as bioethics, law, medicine, philosophy and public health, including Michael Selgelid, Clare Chandler, Marcel Verweij, Alena Buyx, Jonathan Anomaly, Steven J. Hoffman, Julian Savulescu, Otto Cars, and others.

Wednesday, 8 March 2017

Ethics and
Value Challenges in Antibiotic Resistance Management, Policy and Research,
symposium in Gothenburg, November 15-16, 2017. Save the date!

The World
Health Organization identifies antibiotic resistance as a global challenge so
serious that it threatens the fundamental achievement of modern medicine.
Ethics and value conflicts are at the centre of this challenge: understanding
its nature and stakes, identifying adequate social responses, understanding why
policies and actions can be more or less accepted by stakeholders. Underlying
issues regard conflict between individual interests and long term interests of
society; as well as national as opposed to global societal interests in the
short- and long term, how to manage the distribution of benefits and burdens
coming out of efforts to mitigate further resistance development and managing
consequences of established resistance, and responsibly balancing uncertainty
in the face of major public health threats.

The Centre for
Antibiotic Resistance Research (CARe) at the University of Gothenburg started
in 2016 as a cross disciplinary hub for research, education and public outreach
across six faculties, including collaboration with societal and private actors.
More information about CARe is found here: http://care.gu.se

The original CARe team at its inaugural conference in April 12016

Now CARe
presents a 2 day symposium on the theme of Ethics and Value Challenges
in Antibiotic Resistance Management, Policy and Research, November 15-16,
2017. This symposium will house up to 300 participants,
and assemble internationally excellent keynote presenters in ethics, law,
public health and related areas engaged on this topic – including leaders of
recently started major research projects– from Australia, Canada, the
Netherlands, Germany, Sweden, the United Kingdom, and the USA (see program below). The conference is open
and free of charge, but will require pre-registration, details of how to
register will follow.

Alena Buyx
(Christian-Albrechts University of Kiel): How should policy makers, business
and professional practitioners think about the ethical aspects of ABR
management?

Christian
Munthe (University of Gothenburg): Do we have reason to adjust standard
precautionary rules for introduction of new interventions and methods in ABR
policy and other public health emergency settings?

Sverker Jagers
(University of Gothenburg): The role of public trust to balance ethics and
effectiveness in the implementation of global political action